Bergey2016 PDF

Review Article
Management Address correspondence to Dr Gregory K. Bergey, Johns Hopkins School of Medicine, 600 North Wolfe Street,
Meyer 2-147, Department of Neurology, Baltimore, MD 21287, gbergey@jhmi.edu.
of a First Seizure
Relationship Disclosure: Dr Bergey has received
Gregory K. Bergey, MD, FAAN

personal compensation for serving as an associate editor of Neurotherapeutics and has received research support from the
National Institutes of Health.
ABSTRACT Purpose of Review: Assessment of the patient with a first seizure is a common and important
neurologic issue. Less than 50% of patients who have a first unprovoked Unlabeled Use of Products/Investigational
Use Disclosure: Dr Bergey reports no disclosure.
seizure have a second seizure; thus, the evaluation should focus on determining the patient’s risk of seizure
recurrence. Recent Findings: A number of population studies, including some classic reports, * 2016 American
Academy
have identified the relative risk factors for subsequent seizure recurrence. The 2014
of Neurology.
update of the International League Against Epilepsy definition of epilepsy incorporates these findings, and in 2015,
the American Academy of Neurology published a guideline that analyzed the available data. Summary: Provoked
or acute symptomatic seizures do not confer increased risk for subsequent unprovoked seizure recurrence. Multiple
seizures in a given 24-hour period do not increase the risk of seizure recurrence. Remote symptomatic seizures, an
epileptiform EEG, a significant brain imaging abnormality, and nocturnal seizures are risk factors for seizure
recurrence. Antiepileptic drug therapy delays the time to second seizure but may not influence long-term remission.
Continuum (Minneap Minn) 2016;22(1):38–50.
INTRODUCTION
of 2014, the International League Patients presenting with a
first seizure,
Against Epilepsy (ILAE) defines epi- whether as a child or
adult, are often
lepsy as at least two unprovoked sei- quite distressed. When
one considers
zures occurring more than 24 hours that about 10% of the
population will
apart, one unprovoked seizure and a have a seizure at some
time in their
probability of further seizures similar lives but less than half of
these patients
to the general recurrence risk (approx- will have multiple
seizures, the impor-
imately 60% or more) over the subse- tance of proper
assessment is brought
quent 10 years after two unprovoked into focus. The article
“Diagnosis of Epi-
seizures, or the diagnosis of an epilep- lepsy and Related
Episodic Disorders”
tic syndrome.2 The components of this by Erik K. St. Louis,
MD, MS, FAAN, and
definition are drawn from published Gregory D. Cascino, MD,
FAAN,1 in this
studies that are discussed in this article. issue of Continuum
discusses the
Accurately making an early assess- process of making the
diagnosis and
ment avoids unnecessary treatment of proper evaluation, so for
the purpose
patients unlikely to have a second un- of this article, it will be
assumed that
provoked seizure. Indeed, because of the patient has had an
epileptic seizure
the importance of this early evaluation, (either convulsive or
nonconvulsive),
a number of epilepsy centers have es- and the evaluation will
only be men-
tablished first seizure clinics. In these tioned in the context of
findings that
clinics, patients who have experienced influence the risk of
seizure recurrence.
a first seizure are seen promptly by an It is worth repeating,
however, that as
experienced epileptologist with
the 38
www.ContinuumJournal.com February 2016

KEY hope that this early expert assessment
seizures. Seizures due to a preexisting will more appropriately
guide treat-
brain abnormality or disorder (eg, trau- ment. Decisions about
treatment after a
matic brain injury [TBI]) are considered single seizure include
considerations of
remote symptomatic seizures. While some the chance of
having a second seizure,
authors6 group provoked and acute
POINTS h The diagnosis of
epilepsy is appropriately used even after a single unprovoked seizure if the risk of a the consequences of having a second
symptomatic seizures together, some

second
unprovoked seizure, efficacy of medications in pre-
benefit exists in separating these two
seizure is
significant venting future seizures, and the poten-
categories, as will be discussed further.
(approximatel
y 60% tial toxicity of antiepileptic drugs (AEDs).
Sometimes a first seizure and the asso-
or more). The
chance of seizure recurrence is one
ciated EEG findings allow a syndromic
h A very
important part of the most important determinations
classification that indicates likely recur-
of the history
from that will guide treatment decisions.
rence. Obviously, not all patients fit into
patients with a
“first While one must still deal with proba-
these categories; in some, the cause of the bilities, fortunately,
a number of pop-
seizures is unknown even after evaluation. ulation studies exist
that can assist in
In assessing the patient with a “first” this determination. Of
more than 180
seizure, the neurologist must also de-
seizure” is determining whether they have, in fact, had other unrecognized seizures.
practice parameters published by the

termine whether the patient has actually American Academy
of Neurology (AAN),
had multiple seizures. It is common for six deal with initiation
of AED therapy,
patients to seek medical care after the including evaluation of
a first seizure in
first generalized tonic-clonic seizure, children,3 treatment of
the child with a
but they may not have appreciated the first unprovoked
seizure,4 assessment of
significance of myoclonic jerks after a first seizure in adults,5
and the 2015
awakening, nocturnal tongue biting, guideline for the
management of an un-
or brief staring spells (absence or focal provoked first seizure
in adults.6 The
seizures with dyscognitive features). A 2015 guideline is the
most relevant to
careful history will often determine that the discussion in this
article. (Refer to
many patients with newly diagnosed Appendix A for a
summary of the AAN
seizures have actually had multiple evidence-based guideline
for clinicians.)
events. This is particularly true in pa- In framing the discussion, it
is worth-
tients with complex partial seizures and while to review the
classification of a
children with absence seizures. first seizure (Table 2-1).
Provoked sei-
If the patient has had multiple zures are due to identifiable
causes,
seizures, it is important to determine such as medications,
drugs of abuse,
when these seizures occurred over or metabolic causes.
Seizures resulting
time. In a study by Kho and colleagues,7 from acute brain
processes (eg, enceph-
72 patients with multiple seizures in alitis) are classified as
acute symptomatic
a 24-hour period as their first seizure
TABLE 2-1
Classification of a First Seizure
b Provoked seizure (eg, seizure caused by toxin, medication, or metabolic factors)
b Acute symptomatic seizure (seizure cause by acute illness such as stroke,
traumatic brain injury, encephalitis/meningitis)
b Remote symptomatic seizure (seizure caused by preexisting brain injury)
b Seizure associated with epileptic syndrome (eg, juvenile myoclonic epilepsy)
b Other unidentified
Continuum (Minneap Minn) 2016;22(1):38–50 www.ContinuumJournal.com
39

Management of a First Seizure
KEY POINTS h Multiple unprovoked
seizures within a 24-hour period should be considered a single event, and this by itself does not establish the diagnosis of
epilepsy. h After two unprovoked
seizures separated by more than 24 hours occur, the risk of additional seizures is high (more than 60%), the diagnosis of epilepsy
(seizure disorder) is present, and antiepileptic drug therapy is often warranted.
presentation were compared with 425 patients presenting with a single seizure. The recurrence rate
overall was 38% (28% provoked, 38% idiopathic, 53% remote symptomatic); however, those presenting
with multiple seizures in a 24-hour period were no more likely to have seizure recurrence than those
presenting with a single seizure, irre- spective of etiology or treatment (Figure 2-1). The 2014 ILAE
definition incorporates these findings by stipulat- ing “at least two unprovoked seizures occurring more
than 24 hours apart.”2 One might still elect to begin AED therapy (eg, for remote symptomatic sei-
zures), but this decision to treat should not be influenced by multiple seizures in a 24-hour period.
After two unprovoked seizures (more than 24 hours apart), the risk of subsequent seizures increases
dramatically. In a study by Hauser and colleagues8 that prospectively followed 204 patients
Data showing no difference in cumulative chance of seizure recurrence whether patients presented with a single seizure (n = 425)
or multiple seizures (n = 72).
Reprinted with permission from Kho LK, et al, Neurology.
FIGURE 2-1
7
www.neurology.org/content/67/6/1047. B 2006 American Academy of Neurology.
40
after a first unprovoked seizure, the overall risk for a second seizure was only 33%. After a second
seizure, however, the risk of a third unprovoked seizure rose to 76%. This recurrence risk is
incorporated into the ILAE definition. Most recurrences are within 1 year of the second or third seizure.
After a second symptomatic seizure, the risk of a third seizure over 5 years was 87%, compared to 64%
recurrence risk for idiopathic or cryptogenic seizures. In another study in children, the risk of a third
seizure after a second seizure was 72%.9
ANTIEPILEPTIC DRUG PROPHYLAXIS The only evidence supporting AED prophylaxis is in patients
with high-risk head injury in the early posttraumatic period10; this is addressed in an AAN guideline.11
No evidence exists for AED treatment of patients with brain tumors,12

KEY cerebral cavernous hemangiomas, cere-
seizures may recur if the patient is ex- brovascular events, or
craniotomy13 be-
posed again to the provocative agent. fore a first seizure
occurs.
Obviously, if one could accurately predict who would and who would not ANTIEPILEPTIC DRUG
have a second unprovoked seizure, then TREATMENT
INITIATION
specific recommendations could be pro-
POINTS h Except for during the
first week after severe head trauma, no evidence exists to support administration of antiseizure medication After a first seizure
occurs, the fol-
vided for all patients. In reality, only

to prevent a
first lowing factors should be considered
predictions of probabilities of seizure
unprovoked
seizure. in deciding whether or not to start
recurrence can be made. For example,
h Patients with
provoked AED treatment.
the young child with a single convul-

seizures do not have epilepsy and do not Provoked Versus Unprovoked
need seizure
medication Seizures
if the provoking cause can be eliminated.
TABLE 2-2
sion and no risk factors (eg, normal examination, EEG, and imaging) has a relatively low risk of seizure
recurrence. The ILAE definition defines epilepsy as unprovoked seizures. Table 2-2 is a
Type of Seizure partial list of some of the more com-
Simple partial (focal) seizures with only mon causes of
provoked seizures. While
sensory or focal motor symptoms with- on occasion
hypoglycemia can produce
out alteration of consciousness are less focal neurologic
findings, in general,
disabling than complex partial seizures provoked seizures are
generalized
with alteration of awareness. The deci- convulsive events, not
focal seizures.
sion to treat these simple partial (focal) Alcohol-provoked
seizures, either due
minor seizures without alteration of to intoxication or
withdrawal, will not
awareness should be individualized. be focal seizures,
recognizing that in-
The 8-year-old with a focal motor sei- toxication may lower
seizure thresh-
zure of the mouth and an EEG showing old in the patient with
focal brain
centrotemporal spikes consistent with injury. Therefore, a
patient presenting
benign rolandic epilepsy can reason- with symptoms
suggesting either focal
ably be left off medication unless gen- seizures (eg, focal
motor activity, tran-
eralized tonic-clonic seizures occur or sient confusion) or focal
seizures with
recurrent focal seizures produce psy- secondary generalization
should be
chosocial distress. In contrast, the treated as having an
unprovoked sei-
23-year-old with a frontal cortically zure. Provoked seizures
usually do not
based cavernous hemangioma with a warrant AED therapy. In
some instances,
surrounding hemosiderin ring and a prescribed medication is
essential yet
focal motor seizure clinically similar is a cause of provoked
seizures in that
to that of the 8-year-old may warrant patient. AED therapy
may be justified for
therapy because of the risk of second- a period of time. Of
course, provoked
ary generalization and the fact that
Examples of Provoked Seizures
b Alcohol withdrawal
b Barbiturate or benzodiazepine withdrawal
b Metabolic (eg, hyponatremia, hypocalcemia, hypoglycemia, hyperglycemia)
b Drugs of abuse (eg, cocaine, amphetamines, phencyclidine)
b Medications (eg, tramadol, imipenem, theophylline, bupropion)
41

KEY POINTS h Patients over the age of 60 with a new unprovoked seizure should be considered
the consequences of a disabling sei-

on this small group was undetermined zure (eg, focal with
altered awareness,
but certainly may have delayed the time secondarily
generalized seizure) would
to second seizure. Of the 48 patients, be much greater in this
active adult and
five were lost to follow-up before 1
year symptomatic (often
because of the symptomatic nature of
and 16 died before 1 year,
confound- cerebrovascular disease)
the focal seizure. Febrile seizures are
ing analyses. Many first unprovoked
even if the evaluation
another seizure type that typically does
seizures in older adults can be
consid- is unrevealing.
not require therapy. Refer to the article
ered remote symptomatic
seizures. Treat- h Patients with acute
“Febrile Seizures” by Ajay Gupta, MD,14
ment decisions in this age group
should symptomatic seizures
in this issue of Continuum.
also include the living and lifestyle are much
less likely to have subsequent
Patient Age
situation of the patient (eg, active and driving versus long-term care resident). seizures than are patients
with remote symptomatic seizures.
The question of whether the elderly patient with a single unprovoked seizure warrants different
consideration h Patients with acute
symptomatic seizures do not need long-term antiepileptic drug therapy after the period of acute illness unless a subsequent
seizure occurs.
42
Acute Versus Remote Symptomatic Seizures from a child is not fully resolved. The
It is important to consider acute symp- incidence of new-onset
epilepsy is
tomatic seizures separately from re- highest in children and the
older adult.15
mote symptomatic seizures. A study by Elderly patients with
unprovoked sei-
Hesdorffer and colleagues18 compared zures do not have
idiopathic seizures.
262 patients with acute symptomatic Even if imaging is
unrevealing or non-
seizures with 148 patients with a first specific, these seizures,
while classi-
unprovoked seizure due to a static brain fied as due to
unknown etiology, may
lesion (ie, remote symptomatic). They be due to an undefined
cause rather
defined acute symptomatic as within than being idiopathic.
Cerebrovascu-
7 days of stroke or TBI and during the lar disease is the most
common cause
active infection for central nervous sys- of seizures in the
elderly.16 Unprovoked
tem (CNS) infections. Patients with a seizures in elderly
patients should be
first acute symptomatic seizure were considered focal, with or
without sec-
8.9 times more likely to die within 30 days ondary
generalization, even if the pre-
compared to those with a first unpro- sentation is one of only a
generalized
voked seizure. After 30 days, the 10-year convulsive seizure.
A study of all pa-
risk of mortality did not differ between tients in Marshfield,
Wisconsin, over
the two groups. Over a 10-year period, age 50 who
experienced a first seizure
individuals with a first acute symptom- between 1996 and
1998 identified 48
atic seizure were 80% less likely to ex- patients (incidence 162
per 100,000
perience a second unprovoked seizure patient years).17 Of
these, 12 had re-
compared to individuals with a first un- current unprovoked
seizures (ie, epi-
provoked seizure due to a remote symp- lepsy), 14 had a
single seizure and
tomatic cause (Figure 2-2). The etiologies abnormal EEG or
imaging, and 22 had
of acute symptomatic seizures in this a single seizure with
normal studies.
study were stroke (34.7%), TBI (34.7%), During a 12-month
follow-up, 6 of the
and CNS infection (30.6%). The etiol- 22 patients (27%) with
a single seizure
ogies of the first unprovoked remote and a normal evaluation
had a second
symptomatic seizure were stroke seizure. Interestingly, none
of the 14
(68.2%), TBI (25%), and CNS infection patients with
abnormal tests had a sec-
(6.8%). Patients 65 years of age or older ond seizure in the
12-month follow-up
accounted for 31.7% of the patients period, but most of these
patients (87.5%)
with the first acute symptomatic seizure were treated; the
influence of treatment
but almost half (48.7%) of those with a

Risk FIGURE 2-2
of subsequent seizure over 10 years after acute symptomatic seizure during acute illness (eg, stroke, central nervous system
infection, traumatic brain injury) compared with risk of subsequent seizure in patients with remote symptomatic unprovoked
seizure (ie, previous stroke, central nervous system infection, traumatic brain injury).
Reprinted with permission from Hesdorffer DC, et al, Epilepsia.
18
onlinelibrary. wiley.com/doi/10.1111/j.1528-1167.2008. 01945.x/full. B 2009
International League Against Epilepsy.
first unprovoked seizure, with many of this second group being the patients with cerebrovascular
etiologies. In the Hesdorffer study,18 the risk of a subsequent seizure after a stroke was only 33% if the
seizure was acute symptomatic, but 71.5% if unprovoked remote symptomatic. In TBI patients, the risk
of seizure recurrence was 13.4% if acute symptomatic and 46.6% if remote symptomatic, and with CNS
infections, the risk was 16.6% if acute symptomatic and 63.5% if remote symptomatic. The authors of the
study concluded that the prognosis of a first acute symptomatic seizure differs from that of a first
unprovoked seizure when the etiology is stroke, TBI, or CNS infection. Acute symptomatic seizures have
a higher mortality in the first month and lower risk for subsequent seizures than remote symptomatic
seizures, and the authors appropriately concluded that the evidence suggests that acute symp-
43
tomatic seizures are not epilepsy. This is why these acute symptomatic seizures are sometimes grouped
with provoked seizures as in the 2015 AAN guideline.6 While this is appropriate from the standpoint of
implications for treatment, some rationale exists for separating acute symptomatic seizures from other
provoked seizures (eg, metabolic, medications, drugs) since the former can produce cerebral injury and
chronic changes (eg, gliosis, encephalomalacia) that may be associated with later remote symptomatic
seizures, whereas other provoked seizures do not. Case 2-1 provides an example of these considerations
in clinical practice.
STUDIES OF RISK OF RECURRENCE All of the above considerations per- taining to the significance
of a first seizure essentially revolve around the idea of risk of recurrence. Some of the best
KEY POINT h Patients with an
unprovoked remote symptomatic seizure have a high risk of seizure recurrence and often fulfill the International League Against
Epilepsy criteria for the diagnosis of epilepsy.

KEY POINT h An idiopathic seizure
with an EEG pattern of spike-wave discharges is likely to recur and may represent an epileptic syndrome.
Case 2-1 A 27-year-old man presented to the emergency department after an episode of right leg jerking that
progressed to secondary generalization with tongue biting. His past medical history was significant for a history of a
depressed skull fracture 2 years previously. He was treated with prophylactic antiepileptic drugs (AEDs) at the time
of the trauma but he had no seizures, and his levetiracetam had been discontinued shortly thereafter.
His neurologic examination was normal. Brain MRI showed an area of increased cortical and subcortical signal
in the anterior left frontal lobe consistent with his previous injury. EEG revealed no epileptiform activity, but some
mild focal slowing was seen in the left frontocentral region. He acknowledged he had been drinking (four beers)
while watching a sporting event on television with his friends 36 hours prior to the seizure.
Comment. This patient has experienced a first seizure. The remote alcohol intake was probably not enough to
produce an alcohol-withdrawal seizure, and, in any case, his seizure had focal features and provoked seizures are not
focal. His initial treatment at the time of his high-risk (depressed skull fracture) head injury was appropriate since
prophylactic AEDs can reduce the risk of early (but not late) posttraumatic seizures. His treating physicians at that
time were correct in not continuing his levetiracetam after the acute period since no evidence exists that AEDs
prevent late posttraumatic epilepsy. Now, however, he has had a remote symptomatic seizure due to the previous
head injury. His MRI documents this previous injury. That his EEG is nonspecific (ie, not epileptiform) does not
alter the fact that his risk now of seizure recurrence is significant, and the patient should now be placed on long-term
AED therapy. This patient embodies the considerations of risk factors addressed in the text of a remote symptomatic
seizure resulting from a previous high-risk head injury.
epidemiologic studies regarding the risk
tain the risk of a subsequent seizure, of seizure recurrence are
now over
and the cumulative risks of recurrence 25 years old and
predate MRI tech-
for the entire cohort were 16%, 21%, nology. Nevertheless, the
findings from
and 27% at 12, 24, and 36 months, these studies remain
relevant today,
respectively. If the seizures were and, indeed, these studies
were very
deemed idiopathic, only 17% had a important in drafting the
2015 AAN
recurrence at 20 months, rising to 26% guideline. The lack of
imaging with
by 36 months. If the seizures were MRI in these earlier studies
served to
idiopathic with spike-wave discharges underrepresent the
group with remote
on EEG, however, the risk of seizure symptomatic seizures, so
the conclu-
recurrence was 50% at 18 months. If sions in this highest-risk
group remain
the seizure was idiopathic and the pa- valid, and the risk of
patients with a
tient had a sibling with seizures, the negative evaluation
(including MRI)
risk of seizure recurrence was 29% at today might be even
lower than re-
4 months. Age at first seizure, seizure ported. In the landmark
study by
type, and onset with status were not Hauser and colleagues,19
244 patients
risk factors in this study. It is interesting of all ages who
presented with a first
that, in this study and others, whether unprovoked seizure
were followed
an individual had partial (focal) or gen- for a median of 22
months to ascer-
eralized seizures did not
influence the 44

zures. chance of later recurrence. One might
Again, treatment was administered hypothesize that
since focal seizures
in 80% of patients, but no evidence are often remote
symptomatic, they
showed that treatment favorably af- would be more likely to
recur, but
fected seizure recurrence. A history of this has not been
demonstrated, per-
a previous neurologic insult (ie, remote haps because many
primary general-
symptomatic) was associated with a ized seizures have high
recurrence
2.5-fold increased risk of recurrence. rates and some patients
with general-
In this report, risk factors for seizure ized seizures may have
unrecognized
recurrence in patients with idiopathic partial onset.
seizures were: (1) a sibling with epilepsy, In the 1982 Hauser
study,19 patients
(2) generalized spike-wave discharges with remote
symptomatic seizures had
on EEG, and (3) a history of acute symp- a risk of seizure
recurrence of 34% over
tomatic seizures. The latter two risk factors 36 months, but all
of these seizures oc-
increased the risk of seizure recurrence curred in the first 20
months. In patients
to 60% or more. with head trauma, who comprised 37%
Status epilepticus, prior acute symp- of the remote
symptomatic group, the
tomatic seizures, or a Todd paralysis recurrence risk was 40%
at 12 months
increased the risk of seizure recurrence and 46% at 20 months.
Most of these
in those patients with remote symp- patients (69%) were
treated after the
tomatic seizures. These analyses pro- first seizure; no
difference in recurrence
vide additional support for separating was noted between those
treated and
provoked seizures due to drugs or the small number of
untreated patients.
substances that have no influence on Overall, a prior
neurologic insult was
recurrence risk of later unprovoked sei- the most powerful
predictor found. A
zures from acute symptomatic seizures. spike-wave pattern on
EEG was also a
As discussed, acute symptomatic sei- risk factor; a spike-wave
pattern could
zures have a low risk of seizure recur- suggest the possibility
of an epileptic
rence (less than 25%), and chronic syndrome (eg, juvenile
myoclonic epi-
AED treatment is often not warranted. lepsy) with a known
high risk of seizure
But once the patient has a subsequent recurrence.
Interestingly, a focal EEG
unprovoked seizure, a history of a pre- abnormality was not a
predictor in this
vious acute symptomatic seizure in- study by Hauser and
colleagues.19 A
creases the risk of seizure recurrence to positive family history
was also an inde-
60% or more. pendent risk factor in these patients.
These initial 1982 studies were ex-
SEIZURE RECURRENCE IN tended to longer follow-up that
was
CHILDREN subsequently published in 1990.20 These
Interestingly, no population studies have 208 patients were
followed for a mean
demonstrated age as an independent duration of 4 years after
their first un-
risk factor for seizure recurrence. Sei- provoked seizure.
Overall recurrence
zures that begin in childhood are much risks were 14%, 29%,
and 34% at 1, 3,
more likely to be idiopathic than in adults, and 5 years,
respectively, following the
and children are more likely to be diag- first episode. In the
149 patients with
nosed with epileptic syndromes. Both idiopathic seizures, the
recurrence risks
of these factors can influence the chance were 10%, 24%, and
29%, compared to
of seizure remission, a topic that will not recurrence risks of
26%, 41%, and 48%
be addressed here. As mentioned, the at 1, 3, and 5 years,
respectively, for
AAN has a separate guideline for treat- patients with remote
symptomatic sei-
ment of the child with a first unprovoked
45

KEY POINT h Risk factors for seizure
recurrence in children are similar to those in adults, with epileptiform
seizure.4 This is reasonable since the

mal EEG. Interestingly, in children with causes of unprovoked
seizures in chil-
symptomatic unprovoked seizures (eg, dren are different than
those in adults.
structural lesions), an abnormal EEG While children may bike,
swim, and
was not associated with increased
risk; EEG and remote
climb trees, they are not going to be
that is, the increased risk was
conferred symptomatology being
driving, and the risks of injury due to
by the structural lesion. Risk factors
are important factors.
a second seizure may be less than for
similar for early or late seizure recur- an adult. Sudden
unexpected death in
rence.21 In another study by the same epilepsy (SUDEP) is a
concern for pa-
group,22 the 5-year recurrence risk for tients of all ages; no
evidence exists that
children having a first unprovoked treatment after a first
unprovoked sei-
seizure was only 21% if the seizures zure reduces this risk.
Although many
were idiopathic/cryptogenic and the of the second- and
third-generation
EEG was normal. Only 3% of children AEDs have better
cognitive profiles
had a second seizure after 5 years from than the
first-generation agents, medi-
the first. cations can still have effects on learn- ing, and the
taking of daily medication
EFFECT OF TREATMENT ON may be stigmatizing to the
otherwise
RISK OF RELAPSE healthy young child in school.
In assessing the risk of a second seizure, Shinnar and
colleagues9,21 have con-
treating physicians are trying to deter- ducted very thorough
studies of sei-
mine when to start AED therapy. It is zure recurrence in
children. In one study
hoped that AED therapy will provide of 407 children followed
a mean of
seizure control or at least reduce the 6.3 years after an
unprovoked seizure,
risk of a second seizure. As mentioned, 42% had subsequent
seizures, with the
no evidence has shown that prophylac- cumulative risk of 29%
at 1 year rising
tic AED therapy prevents the develop- to 37% at 2 years and
42% at 3 years.9
ment of epilepsy. Does AED therapy Risk factors for seizure
recurrence in
reduce the risk of a second seizure in this group included
remote symptom-
patients who have already had their first atology, abnormal
EEG, seizures occur-
unprovoked seizure? ring during sleep, history of prior febrile
Two randomized trials have attempted seizures, and a Todd
paralysis. An
to answer that question. The First Seizure epileptiform EEG
was more predictive
Trial (FIR.S.T) Group studied 397 pa- of seizure recurrence
than an EEG that
tients, 2 to 70 years of age, 193 of whom was abnormal but
nonspecific. The risk
were randomly assigned to delayed of seizure recurrence with
a normal
treatment.23 The risk of recurrence in the EEG was less than
30% over 5 years.
untreated cohort was 18% at 3 months, This risk rose to 45%
with a nonep-
28% at 6 months, and 51% at 24 months. ileptiform abnormal
EEG and to over
Among the treated cohort, the risk of 60% with an
epileptiform EEG. Focal
relapse was 25% in the first 24 months, slowing was also
associated with a high
suggesting that treatment does lead to risk of seizure
recurrence in these
significant reduction of risk. studies, in contrast to the studies
by
The European Multicenter Epilepsy Hauser and
colleagues.19 In the studies
and Single Seizure Study (MESS) was of Shinnar and
colleagues,9,21 the EEG
an unmasked multicenter randomized was the most important
predictor in
study of immediate versus deferred patients with idiopathic
first seizures.
AED treatment in 1847 patients with Symptomatic first
seizures were more
single seizures or early infrequent un- commonly associated
with an abnor-
provoked seizures.24 Of the 408
patients 46

KEY in MESS who were randomly assigned
ural history of patients receiving treat- to deferred treatment,
26% had recur-
ment. In one large series of over 1000 rence at 6 months and
39% at 2 years,
patients, 37% achieved early (within similar to the FIR.S.T
results. At 5 years,
6 months of initiation of therapy) sus-
POINTS h Antiepileptic drug
therapy after a first unprovoked seizure increases the time to 51% of the untreated MESS cohort had
tained seizure freedom, and 22%

second
seizure. a recurrence of seizures; those patients
achieved delayed (after 6 months of followed for 8 years had a
52% recur-
initiation of therapy) seizure freedom rence rate. In this later
study by Marson
on AED monotherapy.26 The chance and colleagues,24
immediate AED ther-
of achieving seizure freedom declines
h Seizure recurrence in
adults presenting with a first unprovoked seizure is greatest in the first apy increased the time to first seizure,
dramatically from the first to third drug

2 years (21%
to 45% second seizure, and first tonic-clonic
regimen, particularly in patients with
for all
patients). seizure, as well as significantly reduced
focal epilepsy for whom therapy has the time to achieve a
2-year remission
failed because of lack of efficacy, not of seizures, but at 5-year
follow-up, 76%
side effects.26,27 of the patients in the immediate treatment
group and 77% of those in the deferred treatment group were seizure
47 AMERICAN ACADEMY OF

NEUROLOGY PRACTICE free, treatment indicating did not that reduce immediate the long-term AED
GUIDELINES PARAMETERS
AND PRACTICE
remission rate in individuals who had
In 2015, the AAN published an evidence- infrequent or single
seizures.
based guideline on the management of Kim and colleagues25
further ana-
an unprovoked first seizure in adults.6 lyzed the MESS patient
cohort. Using
(Refer to Appendix A for a summary of the 1443-patient
cohort, they developed
the AAN evidence-based guideline for a prognostic model.
The hazard ratio for
clinicians.) As is required with these seizure recurrence in the
untreated arm
evidence-based guidelines, the authors was 1.35 for remote
symptomatic seizures
did an exhaustive review. They identi- and 1.54 for an
abnormal EEG. In de-
fied 2613 articles and selected 281 for veloping their model,
they assigned two
full review. A number of the studies they points for three or
four seizures prior to
used in their analyses have been dis- presentation and one
point each for an
cussed above, but the reader is referred abnormal EEG, a
neurologic disorder,
to the guideline for the complete anal- or two or three seizures
prior to pre-
ysis. Drawing from the best available sentation. The low-risk
group included
published information (Class I and those patients with only a
single seizure.
Class II studies), they found that risk The high-risk group was
more than
of recurrence was greatest in the first three seizures or two or
more risk
2 years and was 21% to 45% for the un- factors. The
remaining patients were
selected patients (Figure 2-3). Patients classified as medium
risk. There was
with a prior brain lesion or insult (re- little benefit to
immediate treatment in
mote symptomatic), an EEG with epi- the low-risk group, but
potential benefit
leptiform abnormalities, a significant in the medium- and
high-risk groups.
brain imaging abnormality, or nocturnal Other studies have
looked at pat-
seizures were at increased risk of seizure terns of treatment
response in newly
recurrence (Table 2-3). Two Class II diagnosed epilepsy in
which all patients
studies supported the increased risk of were treated with
AEDs. While these
nocturnal seizures; certain seizures (eg, studies do not fulfill
the requirements
frontal lobe focal seizures) have a pre- of evidence-based
assessment, they do
disposition to occur at night. The au- provide information
regarding the nat-
thors found evidence that immediate

KEY POINT h Delay in antiepileptic drug initiation until after the second unprovoked seizure does not influence the chance of
long-term remission.
TABLE 2-3
FIGURE 2-3
Percentage of patients with first seizure experiencing a recurrent seizure over time.
Reprinted with permission from Krumholz A, et al, Neurology.
6
www.neurology.org/content/84/16/1705.full. B 2015 American Academy of Neurology.
AED therapy was likely to reduce the risk of a second unprovoked seizure by about 35% over the next 2
years but that delay in initiating therapy until after a second unprovoked seizure did not influence the
chance of long-term remission. The MESS reports discussed above addresses these issues.24,25 The
guidelines state that the risk for ad- verse events from AEDs was 7% to 31%, but the authors
acknowledged that a number of the studies employed first-generation AEDs and that selected second- or
third-generation AEDs could be better tolerated.
Patients at Increased Risk for Seizure Recurrence After First Guideline Seizure: Analysisa
American Academy of Neurology
b Patients with prior brain lesion or insult (remote symptomatic)
b Epileptiform EEG abnormality
b Significant brain-imaging abnormality
b Nocturnal seizure
EEG = electroencephalogram. a Data from Krumholz A, et al, Neurology.6 www.neurology.org/content/84/16/1705.full.
48
In 2003, the AAN published a practice parameter on the treatment of the child with a first unprovoked

seizure.4 Their analyses used only studies that included children, but the authors acknowledged that few
good studies limited to children existed. Having said this, it should be mentioned that age has not been
shown to be an independent variable in multiple studies. Their conclusion was that treatment with an
AED is not indicated for the prevention of epilepsy. Although treatment after a first unprovoked seizure
appears to decrease

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Review Article

Gregory K. Bergey, MD, FAAN

symptomatic seizures together, some

practice parameters published by the

vided for all patients. In reality, only

the young child with a single convul-

the consequences of a disabling sei-

seizure.4 This is reasonable since the

tained seizure freedom, and 22%

dramatically from the first to third drug

47 AMERICAN ACADEMY OF

In 2003, the AAN published a practice parameter on the treatment of the child with a first unprovoked

3. Hirtz D, Ashwal S, Berg A, et al. Practice sociated with

first unprovoked seizure: report of the potential side effects

WNL. 0000000000001487. unrecognized previous

10. Temkin NR, Dikmen SS, Wilensky AJ, et al. A to start

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